Lipid Biomarker Efflux from the Brain following TBI

TBI 后大脑中的脂质生物标志物流出

• 批准号: 9981381
• 负责人: Facundo Martin Fernandez
• 金额: $ 36.07万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981381
• 关键词: Acute; Affect; American; Attention; Biological Markers; Blinded; Blood; Blood - brain barrier anatomy; Brain; Brain Pathology; Cause of Death; Cerebrospinal Fluid; Classification; Clinical; Clinical Management; Closed head injuries; Collection; Diagnosis; Diagnostic; Diffuse; Event; Female; Free Radicals; Goals; Head; Health; Health Care Costs; Heterogeneity; Hydrophobicity; Inflammation; Injury; Kinetics; Lipids; Liquid substance; Lymph; Mass Spectrum Analysis; Measurement; Membrane; Modeling; Molecular; Myelin; Neuraxis; Neuroglia; Neurons; Organ; Oxidative Stress; Pathology; Pattern; Peripheral; Permeability; Persons; Population; Property; Proteins; Rattus; Research; Resolution; Route; Sampling; Serum; Severities; Standardization; Techniques; Time; Tracer; Traumatic Brain Injury; United States; Work; base; biomarker panel; brain tissue; candidate marker; cost; disability; economic cost; glymphatic system; imaging study; improved; individual response; injured; lymphatic vessel; male; metabolomics; novel; outcome forecast; oxidation; spectroscopic imaging

Project Summary: Lipid Biomarker Efflux from the Brain following TBI, LaPlaca, M.C., Fernández, F.M. Traumatic brain injury (TBI) is a major health problem in the US and worldwide, affecting at least 2.5 million Americans every year. TBI is extremely variable from person to person, making the standardization of injury classification and diagnosis challenging. Fluid biomarkers can potentially provide personalized information, yet none are currently approved for TBI diagnosis or prognosis. Most of the TBI biomarker candidates are proteins that are likely released from dying neurons and glial cells, yet the brain has a very high lipid content compared to other organs, and is vulnerable to oxidative stress, leaving brain lipids extremely vulnerable to free radical attack. Furthermore, lipids may leak out of the brain more readily than proteins, rendering them ideal candidates for peripheral diagnostics. The route for biomarker clearance from the brain to the blood has been assumed to be primarily via the blood brain barrier (BBB), however a glymphatic route for molecule clearance is now recognized, changing the focus from BBB-only transport to one of potentially multiple efflux routes. Given the promise of TBI-specific lipid biomarkers and the unknown dynamics of lipid biomarker release, there is a need to better understand lipid efflux routes following TBI. The objective of the proposed work is to identify novel lipid biomarkers for TBI diagnosis and the routes by which they exit the brain as a function of time and injury severity. The overall hypothesis is that TBI-specific lipids pass through BBB and glymphatic routes to the blood, and that these efflux kinetics will vary based on injury severity and lipid properties. Three mutually- informing aims will be pursued: Aim1) Identify a serum lipid biomarker panel that is reflective of TBI severity and pathology. It is hypothesized that the number and population of altered lipids in the brain and blood will indicate injury severity; Aim 2) Determine brain efflux routes and temporal efflux dynamics of lipids after TBI. It is hypothesized that more than one route of brain clearance of TBI-generated lipid biomarkers exists and the efflux dynamics depend on lipid size and time post-injury; and Aim 3) Develop a model to predict TBI severity based on serum lipid biomarker levels. It is hypothesized that a compartmental model using parameters from Aims 1 and 2 will allow prediction of TBI severity from lipid biomarker profiles in serum. Discovery metabolomics techniques identifying lipids in serum that successfully discriminates between injured and uninjured rats will be expanded to include surveillance in cerebrospinal fluid and lymph in the acute and subacute time post-TBI for a range of injury severities in both male and female rats. Through this research, we expect to identify novel lipid biomarker panels and determine the major route(s) for their release from the brain. This is significant and novel because, while biomarkers provide a unique window into secondary injury events, changes in efflux patterns directly impact clinical interpretation and implementation.

项目摘要：TBI，Laplaca，M.C。，Fernández，F.M。大脑中的脂质生物标志物外排。 创伤性脑损伤（TBI）是美国和全球的主要健康问题，至少影响250万 每年的美国人。 TBI的人与人之间的变化极大，使受伤的标准化 分类和诊断挑战。流体生物标志物可能会提供个性化信息，但 目前，没有人批准用于TBI诊断或预后。大多数TBI生物标志物候选者是蛋白质 可能是由垂死的神经元和神经胶质细胞释放的，但是大脑的脂质含量很高。 到其他器官，容易受到氧化胁迫的影响，使脑脂质极易受到自由基的影响 攻击。此外，脂质可能比蛋白质更容易从大脑中泄漏出来，从而使它们理想 候选人的外围诊断。从大脑到血液的生物标志物清除途径已经 假定是通过血脑屏障（BBB）为主要的，但是分子清除的糖基途径 现在被认可，将重点从仅BBB运输转变为潜在的多个外排路线之一。 鉴于TBI特异性脂质生物标志物和脂质生物标志物释放的未知动力学的承诺， 需要更好地了解TBI后的脂质外排路线。拟议工作的目的是确定 用于TBI诊断的新型脂质生物标志物以及它们作为时间和时间的函数退出大脑的途径 受伤严重程度。总体假设是TBI特异性的脂质通过BBB和糖基途径到达 血液，这些外排动力学会根据损伤的严重程度和脂质特性而变化。三个互惠 将追求目标：AIM1）确定反映TBI严重性的血清脂质生物标志物面板 和病理。假设大脑和血液中脂质变化的数量和种群将 表明受伤严重程度； AIM 2）确定TBI后脂质的脑外排路线和暂时的外排动力学。它 假设，有多种TBI生成的脂质生物标志物的脑清除途径存在 排出动力学取决于脂质的大小和伤害后的时间；目标3）开发一个模型来预测TBI严重性 基于血清脂质生物标志物水平。假设使用来自来自的参数的隔室模型 目标1和2将允许血清中脂质生物标志物谱的TBI严重程度预测。发现 代谢组学鉴定血清中脂质的技术成功区分受伤和 未受伤的大鼠将扩大以包括脑脊液的监测和急性和淋巴 TBI后急性时间用于男性和雌性大鼠的一系列损伤严重性。通过这项研究，我们 期望识别新型的脂质生物标志物面板，并确定其从大脑释放的主要途径。 这是重要而新颖的，因为尽管生物标志物为次要伤害事件提供了独特的窗口，但 外排模式的变化直接影响临床解释和实施。